Mechanism of synergic interaction of Syk inhibitors on antimalarial artemisinin activity

The primary objective of malaria treatment is to eradicate the disease, which involves rapid and complete elimination of the Plasmodium parasite from the patients’ blood. Artemisinin combination therapies (ACTs) are the mainstay of recommended treatment for P. falciparum malaria and as no alternatives to artemisinin derivatives are expected to enter the market for several years, their efficacy must be preserved. Unfortunately, the resistance to ACTs, is a major thread for the control and elimination of malaria due to P. falciparum. The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs. Recently it has been demonstrated that Syk inhibitors represent a new class of antimalarial drugs which suppress merozoite egress by inhibiting the host target, a factor that cannot be mutated by the parasite to evolve drug resistance. In this study, our aim is to evaluate the in vitro combination activity of Syk inhibitors with artemisinins and understand their mechanistic interaction. The results showed a high synergistic combination activity between all tested Syk inhibitors with artemisinins against P. falciparum. The combination index analysis indicated the following Syk inhibitors as the most synergistic with Artemisinins: P505-15, R406 and Imatinib. Furthermore, we observed that Syk inhibitors produce a massive accumulation of hemichromes in the parasitized erythrocytes, this in turn triggers the activation of artemisinins and causes a marked synergistic effect when administered in combination. The synergic effect of Syk inhibitors is based on a novel mechanism of action acting selectively on the parasitized erythrocytes which allows the artemisinins to be activated quicker and more efficiently. The concentrations of Syk inhibitors needed to synergize artemisinins is 5-20 fold lower than the IC50 measured as a direct effect on parasite growth. These concentrations correspond to very well tolerated dosages and can be rapidly reached after oral administration. In conclusion, our results potentially suggest Syk inhibitors as a strategic class of partner drugs for a new ACT.